The inspection revealed that your BBG Injection drug product is adulterated within the meaning of section 501(a)(1) of the Act [21 U.S.C. § 351(a)(1)] in that it consists in whole or in part of any filthy, putrid, or decomposed substance. This inspection further revealed that this drug is adulterated within the meaning of Section 501(c) of the Act [21 U.S.C. 351(c)], in that its strength differs from, or its purity or quality falls below, that which it purports or is represented to possess. Furthermore, this drug and all sterile drugs compounded by your firm are also adulterated under section 501(a)(2)(A) of the Act [21 U.S.C. § 351(a)(2)(A)], in that they have been prepared, packed, or held under insanitary conditions whereby they may have been contaminated with filth, or whereby they may have been rendered injurious to health.

In addition, BBG Injection drug products compounded by your firm were misbranded within the meaning of Section 502(a) of the Act [21 USC 352(a)] because their labeling was false or misleading.

ADULTERATION CHARGES

FDA laboratory analysis identified the presence of Fusarium incarnatum-equiseti species complex, as well as other microorganisms, in samples of your compounded drug product BBG Injection collected during the inspection. This Fusarium incarnatum-equiseti species complex genetically matched Fusarium clinical isolates from patients who developed fungal endophthalmitis after the administration of your compounded BBG Injection. These findings demonstrate that lots of Brilliant Blue G are adulterated within the meaning of section 501 (a)(1) of the Act [21 U.S.C. § 351 (a)(1)], in that it consists in whole or in part of any filthy, putrid, or decomposed substance. Furthermore, these BBG Injection drug products were labeled as being sterile, and are therefore adulterated within the meaning of Section 501 (c) of the Act [21 U.S.C. 351(c)], in that its strength differs from, or its purity or quality falls below, that which it purports or is represented to possess.

Also, multiple bacterial and fungal species were found in several locations within one of your firm's ISO Class 5 laminar flow hoods and the ISO Class 7 clean room where you compound sterile drugs. These products are adulterated within the meaning of Section 501(a)(2)(A) of the Act [21 USC§ 351(a)(2)(A)] in that they were prepared, packed, or held under insanitary conditions whereby they may have been contaminated with filth, or whereby they may have been rendered injurious to health. The inspection revealed additional insanitary conditions under which your firm compounds sterile drugs, including but not limited to, the following:

1. A compounding technician twice left and re-entered the cleanroom without changing the lab coat, foot covers, or any other personal protective equipment (PPE). This practice of re-entering the cleanroom without changing into new PPE creates an unacceptable hazard as the technician increased the potential for conveying uncontrolled microbial load from the unclassified pharmacy room into the cleanroom environment and the laminar flow hoods where sterile products are manipulated.

2. While putting on sterile gloves, a compounding technician touched the outside of one of the gloves with a bare hand before putting on the second glove. This breach of asepsis created a significant microbial contamination hazard from bare skin when the technician then proceeded to perform sterile drug compounding in the laminar flow hood.

3. A compounding technician was observed to touch the hood's outer surfaces with both gloved hands and then began sterile compounding. This technician's unnecessary actions presented a significant risk that microorganisms from the hood's outer surfaces would be transferred into the laminar flow hood and contaminate compounded sterile products. Notably, environmental sampling of the outer surfaces of the hood collected two days earlier found multiple sites contaminated with microorganisms.

MISBRANDING CHARGES

Your contaminated BBG drug products are indicated for ophthalmic use through intraocular injection. Drugs with this route of administration are required to be sterile. Although your BBG drug products were labeled as being sterile, clinical and drug product samples indicate that BBG drug products were contaminated with Fusarium. Therefore, the contaminated drug products bearing this labeling were misbranded under Section 502(a) of the Act because the labeled sterility claim and directions for intraocular administration misleadingly implied the products were sterile.

Neither this letter nor the observations noted on the FDA-483 is intended to be an all-inclusive list of the deficiencies that may exist at your facility. In addition, the Agency may send further correspondence based upon continued review of the inspectional findings. You are responsible for investigating and determining the causes of the deviations identified above and for preventing their recurrence and the occurrence of other deviations. We note that the following observations, if adequately addressed, could help prevent the violations of the Act described above:

1. Your firm failed to adequately assess compounding personnel aseptic practices. For example, there was no indication that fingertip sampling, demonstrating competency in proper hand hygiene and garbing procedures, were performed as part of either an initial competency evaluation or a routine monitoring program. As direct human touch contamination is the most likely source of introducing microorganisms into sterile products, your firm's programs and practices were inadequate to assure that personnel were capable of maintaining asepsis to prevent serious microbial contamination hazards to the ISO Class 5 laminar flow hood environment, and ultimately, to product sterility.

2. In your firm's performance of environmental monitoring tests, you failed to use a fungal growth media and your firm was not able to reliably detect the presence of fungi in the environment. It should be noted that when environmental samples of your cleanroom were cultivated in suitable growth media to recover fungi, multiple fungal species were identified at various sampling sites.

3. Your firm does not perform environmental viable airborne particle testing under routine operational conditions to evaluate the competency of compounding personnel work practices. Furthermore, your SOP 3.060, "Environmental Monitoring of the Aseptic Compounding Area: Microbial Organism," is deficient in that it does not contain an environmental monitoring sampling plan that is based upon a risk assessment of the compounding activities performed. For example, the sampling plan does not specify method of collection, type of microbial growth media to be used, volume of air sampled, when samples are to be taken, or action or alert levels. You lack assurance that the current state of your ISO Class 7 cleanroom; ISO Class 5 laminar flow hoods; and personnel cleansing, garbing, and compounding practices sufficiently minimize airborne viable particles to prevent microbial contamination of your products during routine operations.

4. Your firm does not perform nonviable (particulates) monitoring in the ISO Class 5 area of your cleanroom. Furthermore, your firm does not conduct smoke studies for your laminar flow hoods to demonstrate unidirectional air flow and sweeping action over and away from compounded drug products under dynamic conditions. You have no assurances that the laminar flow hoods are Working properly to keep particles shed by personnel from contaminating compounded sterile drugs.

5. The ceiling of your firm's clean room consists of inlaid panels which have neither been impregnated with a polymer to render them impervious and hydrophobic, nor caulked around each perimeter to seal them to the support frame. As such, these areas are prone to the accumulation of dust and other particles and are potential sites for microbial contamination of your ISO Class 7 cleanroom.

It is your responsibility to assure that your sterile compounding operations comply with all requirements of federal law and FDA regulations.

You should take prompt action to correct the deviations detailed in this letter. Failure to promptly correct these deviations may result in legal action without further notice including, without limitation, an injunction. Other federal agencies may take this Warning Letter into account when considering the award of contracts. FDA may re-inspect to verify corrective actions have been completed.

We acknowledge your firm's response of June 15, 2012 and your continued commitment to recall all human and veterinary drug products compounded since November 21, 2012 and to suspend sterile compounding operations at least until observations documented on the Form FDA 483 issued to your firm on May 11, 2012, have been adequately resolved. If at a later date your firm decides to resume sterile compounding operations, FDA strongly recommends that you retain an independent expert, who is knowledgeable and experienced in sterile compounding, to assist you in implementing appropriate sterile compounding procedures and conditions, as required by law. In addition, we acknowledge your commitment to notify FDA well in advance of any resumption of sterile compounding operations and request that you submit all relevant SOPs to the Agency at that time for our review.

Within fifteen working days of receipt of this letter, please notify this office in writing of the specific steps that you have taken to correct violations. Include an explanation of each step being taken to prevent the recurrence of violations and copies of supporting documentation. If you cannot complete corrective action within fifteen working days, state the reason for the delay and the date by which you will have completed the correction. Your reply should be sent to the attention of: Winston Alejo, Compliance Officer, Food and Drug Administration 555 Winderley Place, Suite 200, Maitland, Florida 32751. If you have questions regarding any issues in this letter, please contact Mr. Alejo at (407) 475-4731.